PROJECT SUMMARY ABSTRACT Targeted protein degradation controlled by the ubiquitin proteasome system is involved in virtually all aspects of cellular physiology, including development, signal transduction and aging. In addition, dysfunction in ubiquitin mediated protein degradation is causative in diseases ranging from cancer to neurodegenerative disorders. E3 ligases impart selectivity on the ubiquitin system by specifying target proteins for ubiquitylation and degradation. The Cullin RING E3 ligases (CRLs) represent the largest E3 family in humans. CRLs rely on large families of substrate receptors to specify which substrates become ubiquitylated. Connecting E3 ligases with their cognate substrates, akin to mapping kinase and transcription factor targets, represents the key challenge to defining the function of specific enzymes, and provides mechanistic insight into the role of individual enzymes in cellular homeostasis and disease. The Cullin ligase SCF/CRL1 utilizes a family of 69 substrate receptors termed F-box proteins. The SCF is essential for cell cycle progression, checkpoint function and genome stability. This proposal is focused on Cyclin F, a cell cycle regulated substrate receptor, F-box protein for the SCF. Using Cyclin F as a paradigm, we will interrogate the broader role of CRLs in cell cycle control. By leveraging our expertise in biochemistry, cell and systems biology we will gain a deep understanding of Cyclin F function, and by extension the CRLs, in cell proliferation and genome stability, and its potential contribution to malignancies.